AT ECTRIMS 2016
LONDON (FRONTLINE MEDICAL NEWS) – Siponimod delayed disability progression in patients with secondary progressive multiple sclerosis, according to top-line findings from the phase III EXPAND study.
Siponimod reduced the primary endpoint of the time to 3-month confirmed disease progression (CDP) assessed via the Expanded Disability Status Scale (EDSS) by 21%, compared with placebo (P = .013).
“It is reassuring that this primary outcome is supported by an important secondary outcome of the time to CDP at 6 months,” presenting author Ludwig Kappos , MD, of University Hospital Basel (Switzerland), said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
He reported that a 26% reduction in the 6-month CDP was also observed comparing the active and placebo treatments (P = .006) in the multicenter, randomized, double-blind trial that involved 1,646 patients “with the whole spectrum” of secondary progressive multiple sclerosis (SPMS).
The findings build on those of the phase II BOLD study in patients with relapsing-remitting MS (RRMS) ( Lancet Neurol. 2013;12[8]:756-67 ) and showed a reduction in relapse rates and a reduction in the number of brain lesions seen on MRI scans for siponimod, compared with placebo.
Recently reported data from the 24-month extension of the BOLD phase II trial ( JAMA Neurol. 2016;73[9]:1089-98 ) also showed that disease activity was low in patients treated with siponimod, and that there were no new safety signals. D ose reduction during initiation mitigated cardiac adverse effects, an approach that was also used successfully in the phase III study.
Siponimod is a once-daily oral treatment being developed by Novartis for the treatment of MS. Like fingolimod (Gilenya), which is licensed for the treatment of RRMS, siponimod is a selective sphingosine 1-phosphate receptor (S1P) modulator. Unlike fingolimod, which targets S1P subtypes 1, 3, 4, and 5, siponimod only targets the S1P 1 and 5 subtypes.
Fingolimod is also known to cause temporary changes in heart rate, heartbeat, and blood pressure, which necessitates early electrocardiographic monitoring during the first 6 hours when the drug is first given. At the present time, it doesn’t seem that siponimod will have unwanted cardiac effects, but longer-term follow-up data are needed.
“Adverse events were as you would expect with an S1P receptor modulator,” Dr. Kappos said, noting that there was nothing new. Overall, any adverse event occurred in 88% of actively-treated and 81% of placebo-treated patients. The rate of serious adverse events was similar in the siponimod (3.8%) and placebo (3.7%) arms, and a similar percentage of patients were reported to have infections (48% and 49%, respectively).
Analysis of all the various secondary endpoints is still ongoing; Dr. Kappos noted that the primary endpoint data had just recently become available. Some initial findings, however, show benefit for siponimod over placebo.
The change in T2 lesion volume from baseline to both 12 and 24 months was significantly less with siponimod than with placebo, at a 79.1% lower average change (P less than .0001).
The annualized relapse rate was reduced by 55% with the active treatment versus placebo, and there was less percent change in brain volume with active therapy versus placebo from baseline to 12 and 24 months’ follow-up (23.4% lower average change, P = .0002).
The time to 3-month confirmed worsening by 20% or more from baseline in the timed 25-foot walk test was reduced by 6.2%. Although not significant, the trend was “in the right direction,” Dr. Kappos said.
The mean age of recruited patients was 48 years, with an average duration of MS of 16-17 years, and just under 4 years since their conversion to SPMS. Baseline EDSS was a mean of 5.4, around 35%-37% had one or more relapses in the 2 years before screening, and 20% had gadolinium-enhancing lesions at baseline.
A variety of predefined subgroup analyses showed a benefit for siponimod over placebo. These included analyses looking at the effect by the number of gadolinium-enhancing lesions at baseline, previous disease-modifying treatment, whether patients’ MS was rapidly progressing, whether patients’ disease was moderate or severe, the baseline EDSS, and the duration of MS since the first recognition of symptoms.
“What is the optimal patient population?” an audience member asked Dr. Kappos during the Q&A period following his presentation at the ECTRIMS meeting. He responded: “I think younger patients with the more active disease will certainly be the best candidates.” But, he added, it was reassuring to note that the drug seems to work equally well in all patient subtypes.
Novartis funded the study. Dr. Kappos disclosed that his institution has received financial support for research purposes from multiple MS drug manufacturers – including Novartis – and charitable organizations.
